Compositions and methods for treating diverticulitis and related disorders

ABSTRACT

The present disclosure is in the field of pharmaceutical compositions suitable for the treatment of diseases in mammals. The disclosure provides novel compositions comprising non-pathogenic fecal microbes for treating recurrent diverticulitis and related diseases. The disclosure also provides methods for treating a subject with the compositions disclosed herein.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. Non-Provisional applicationSer. No. 16/603,170, filed Oct. 4, 2019, which is a national phase under35 U.S.C. § 371 of International Application No. PCT/US2018/026074,filed on Apr. 4, 2018, which claims priority to U.S. ProvisionalApplication No. 62/482,159, filed on Apr. 5, 2017. Each of theseapplications are incorporated by reference herein in their entirety.

FIELD

The present disclosure relates to pharmaceutical compositions andmethods suitable for treating gastrointestinal (GI) disorders, such asrecurrent diverticulitis.

BACKGROUND

Mammals harbor diverse microbial species in their gastrointestinal (GI)tracts. Interactions between these microbes and between microbes and thehost, e.g. the host immune system, shape a microbiota. A healthymicrobiota provides the host with multiple benefits, includingcolonization resistance to a broad spectrum of pathogens, essentialnutrient biosynthesis and absorption, and immune stimulation thatmaintains a healthy gut epithelium and an appropriately controlledsystemic immunity. An unbalanced microbiota (also called ‘dysbiosis’ ordisrupted symbiosis) may lose its function and result in increasedsusceptibility to pathogens, altered metabolic profiles, or induction ofproinflammatory signals that can lead to local or systemic inflammationor autoimmunity. Additionally, such a disrupted microbiota may beinfected by incoming pathogen or pathogens, which can cause pain,diarrhea, gas, constipation among other symptoms. Hence. the intestinalmicrobiota plays a significant role in the pathogenesis of manydisorders such as pathogenic infections of the gut.

Implantation or administration of human colonic microbiota into thebowel of a sick patient is called Fecal Microbiota Transplantation(FMT), also commonly known as fecal bacteriotherapy. FMT is believed torepopulate the gut with a diverse array of microbes that control keypathogens by creating an ecological environment inimical to theirproliferation and survival. It represents a therapeutic protocol thatallows a fast reconstitution of a normal compositional and functionalgut microbial community.

FMT has been used to treat Clostridium difficile infection (CDI). FMThas also been suggested in treating other gut infective agents such asE. coli and Vancomycin resistant Enterococci (VRE). It entails infusionsthrough a colonoscope, an enema or via a nasojejunal tube of humanmicrobiota either in the form of homogenised stool, or cultured stoolcomponents such as Clostridia, to implant in the colon and therebydisplace or eradicate pathogenic bacteria, e.g., C. difficile.

Diverticular disease includes a spectrum of conditions ranging fromasymptomatic diverticular disease, to symptomatic uncomplicateddiverticular disease, and complicated diverticular disease that includesacute and chronic diverticulitis. Diverticulitis is defined as aninflammation of one or more diverticula, which are small pouches createdby herniation of the mucosa into the wall of the colon. Diverticulitispatients typically present with symptoms of pain of the lower leftquadrant, fever, nausea and vomiting, or abnormal bowel habits(constipation or diarrhea). Complicated diverticulitis may also beassociated abscess, phlegmon, fistula, stricture, stenosis, obstruction,bleeding, or perforation.

Diverticulitis is generally considered a disease of the elderly, but asmany as 20% of patients with diverticulitis are younger than 50 years.Diverticulitis becomes more common after the age of 40, with riskcontinuing to increase with age. Certain drugs such as ibuprofen,naproxen, steroids, and opiates can increase diverticulitis risk. In itschronic form, patients may have recurrent bouts of low-grade or overtdiverticulitis. In the United States, there are more than 200,000 casesof Diverticulitis per year.

More information on diverticulosis and diverticulitis can be found inthe following references: Klarenbeek et al., Int J Colorectal Dis (2012)27:207-14; Tursi, Ther Adv Chronic Dis. (2013) 4(6): 277-86; Tursi etal., Aliment Pharmacol Ther (2013) 38: 741-751; Andeweg et al., Dig Surg(2013) 30:278-92; Tan et al., International Journal of Surgery (2016)26:43-52.

Current attempts for treating relapsing diverticulitis can range frommaintaining a high-fiber diet, rest and antibiotics, for mild cases tosurgery for severe and recurring (relapsing) diverticulitis. There is aneed for more effective treatments for recurrent diverticulitis that areeasier to administer.

SUMMARY

The present disclosure provides compositions, methods, and dosingregimens for treating or preventing recurrent diverticulitis.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering to the subject a pharmaceutically active dose ofa therapeutic composition comprising or derived from live non-pathogenicfecal bacteria or a sterile fecal filtrate. In one aspect, a sterilefecal filtrate originates from a donor stool. In another aspect, asterile fecal filtrate originates from cultured microorganisms.

In another aspect, this disclosure provides use of a compositioncomprising live non-pathogenic fecal bacteria in the manufacture of amedication for the treatment of recurrent diverticulitis.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering orally to the subject a pharmaceutically activedose of a therapeutic composition comprising live, non-pathogenic,synthetic bacterial mixture or live, non-pathogenic, purified orextracted, fecal microbiota, where the dose is administered at a dosingschedule of at least once or twice daily or at least once or twiceweekly for at least three, eight, ten, or twenty consecutive weeks.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering orally to the subject a pharmaceutically activedose of a therapeutic composition comprising a liquid, frozen,lyophilized, or encapsulated sterile fecal filtrate, where the dose isadministered at a dosing schedule of at least once or twice daily or atleast once or twice weekly for at least three, eight, ten, or twentyconsecutive weeks.

In one aspect, a method achieves a remission, cure, response, orresolution rate of recurrent diverticulitis of at least about 80%.

In an aspect, a fecal microbiota in a therapeutic composition comprisesa donor's substantially entire and non-selected fecal microbiota,reconstituted fecal material, synthetic fecal material.

DETAILED DESCRIPTION

Unless defined otherwise herein, terms are to be understood according toconventional usage by those of ordinary skill in the relevant art.

As used herein, the term “treating” refers to (i) completely orpartially inhibiting a disease, disorder or condition, for example,arresting its development; (ii) completely or partially relieving adisease, disorder or condition, for example, causing regression of thedisease, disorder and/or condition; or (iii) completely or partiallypreventing a disease, disorder or condition from occurring in a patientthat may be predisposed to the disease, disorder and/or condition, buthas not yet been diagnosed as having it. Similarly, “treatment” refersto both therapeutic treatment and prophylactic or preventative measures.

As used herein, “therapeutically effective amount” or “pharmaceuticallyactive dose” refers to an amount of a composition which is effective intreating the named disease, disorder or condition.

As used herein, “microbiota,” and “flora” refer to a community ofmicrobes that live in or on a subject's body, both sustainably andtransiently, including eukaryotes, archaea, bacteria, and viruses(including bacterial viruses (i.e., phage)). A non-selected fecalmicrobiota refers to a community or mixture of fecal microbes derivedfrom a donor's fecal sample without selection and substantiallyresembling microbial constituents and population structure found in suchfecal sample.

As used herein, a “sterile fecal filtrate” or a “non-cellular fecalfiltrate” refers to a liquid component of a fecal material, where theliquid component is free or substantially free of cell-based livingorganisms (e.g., bacteria, fungi, or their spores), but retainsbacteriophages and non-cellular biological materials. Preferably, anon-cellular or sterile fecal filtrate is also free of viruses foreukaryotic host cells.

As used herein, “remission, cure, or resolution rate” refers to thepercentage of patients that are cured or obtain remission or completeresolution of a condition in response to a given treatment. Remission,cure, or resolution of recurrent diverticulitis refers to completecessation of one or more symptoms that a patient manifests prior toreceiving a treatment described here. Such symptoms can include, but arenot limited to left lower quadrant pain, abnormal bowel habits, nausea,vomiting, constipation, diarrhea, flatulence, bloating, abscess,phlegmon, fistula, stricture, stenosis, obstruction, bleeding, andperforation. Remission, cure, or resolution can be further confirmed byendoscopic and mucosal healing.

As used herein, “response rate” refers to the percentage of patientsthat respond positively (e.g., reduced severity or frequency of one ormore symptoms) to a given treatment.

As used herein, “eukaryotic” refers to belonging to a cell that containsa nucleus and membrane-bound organelles.

As used herein, “bacteria,” “bacterium,” and “archaea” refer tosingle-celled prokaryotes that lack membrane bound nuclei and lackorganelles.

As used herein, “colony forming units” (cfu) refers to an estimate ofthe number of viable microorganism cells in a given sample.

As used herein, “viable” means possessing the ability to multiply.

As used herein, “fecal bacteria” refers to bacteria that can be found infecal matter.

As used herein, “isolated” or “purified” refers to a bacterium or otherentity or substance that has been (1) separated from at least some ofthe components with which it was associated when initially produced(whether in nature or in an experimental setting), and/or (2) produced,prepared, purified, and/or manufactured by the hand of man. Isolated orpurified bacteria can be separated from at least about 10%, about 20%,about 30%, about 40%, about 50%, about 60%, about 70%, about 80%, about90%, or more of the other components with which they were initiallyassociated.

As used herein, “cytotoxic” activity or bacterium includes the abilityto kill a bacterial cell, such as a pathogenic bacterial cell. A“cytostatic” activity or bacterium includes the ability to inhibit,partially or fully, growth, metabolism, and/or proliferation of abacterial cell, such as a pathogenic bacterial cell.

As used herein, the terms “pathogen” and “pathogenic” in reference to abacterium or any other organism or entity includes any such organism orentity that is capable of causing or affecting a disease, disorder orcondition of a host organism containing the organism or entity.

As used herein, “spore” or a population of “spores” includes bacteria(or other single-celled organisms) that are generally viable, moreresistant to environmental influences such as heat and bacteriocidalagents than vegetative forms of the same bacteria, and typically capableof germination and out-growth. “Spore-formers” or bacteria “capable offorming spores” are those bacteria containing the genes and othernecessary abilities to produce spores under suitable environmentalconditions.

As used herein, a “combination” of two or more bacteria includes thephysical co-existence of the two bacteria, either in the same materialor product or in physically connected products, as well as the temporalco-administration or co-localization of the two bacteria.

As used herein, “subject” refers to any animal subject including humans,laboratory animals (e.g., primates, rats, mice), livestock (e.g., cows,sheep, goats, pigs, turkeys, chickens), and household pets (e.g., dogs,cats, rodents, etc.). The subject or patient may be healthy, or may besuffering from an infection due to a gastrointestinal pathogen or may beat risk of developing or transmitting to others an infection due to agastrointestinal pathogen.

As used herein, “Shannon Diversity Index” refers to a diversity indexthat accounts for abundance and evenness of species present in a givencommunity using the formula

$H = {- {\sum\limits_{i = 1}^{R}{p_{i}\ln\; p_{i}}}}$where H is Shannon Diversity Index, R is the total number of species inthe community, and p_(i) is the proportion of R made up of the ithspecies. Higher values indicate diverse and equally distributedcommunities, and a value of 0 indicates only one species is present in agiven community. For further reference, see Shannon and Weaver, (1949)The mathematical theory of communication. The University of IllinoisPress, Urbana. 117 pp.

As used herein, “antibiotic” refers to a substance that is used to treatand/or prevent bacterial infection by killing bacteria, inhibiting thegrowth of bacteria, or reducing the viability of bacteria.

As used herein, an “intermittent dosing schedule” means that that atherapeutic composition is administered for a period of time followed bya period of time (a treatment period) where treatment with suchtherapeutic composition is withheld (a rest period). Intermittent dosingregimens can be expressed as treatment period in days or weeks/restperiod in days or weeks. For example, a 4/1 intermittent dosing schedulerefers to an intermittent dosing schedule where the treatment period isfour weeks/days and the rest period is one week/day.

As used herein, a “continuous dosing schedule” refers to a dosingschedule where a therapeutic composition is administered during atreatment period without a rest period. Throughout the treatment periodof a continuous dosing schedule, a therapeutic composition can beadministered, for example, weekly, daily, or every other day, or everythird day. On a day when a therapeutic composition is administered, itcan be administered in a single dose, or in multiple doses throughoutthe day.

As used herein, “dosing frequency” refers to the frequency ofadministering doses of a therapeutic composition in a given time. Dosingfrequency can be indicated as the number of doses per a given time, forexample, once per day, once a week, or once in two weeks.

As used herein, “dosing interval” refers to the amount of time thatelapses between multiple doses being administered to a subject.

Diverticula are small mucosal herniations protruding through theintestinal layers and the smooth muscle along the natural openingscreated by the vasa recta or nutrient vessels in the wall of the colon.True diverticulae contain all layers of the gastrointestinal wall(mucosa, muscularis propria, and adventitia) (e.g., Meckeldiverticulum). False diverticulae, or pseudo-diverticulae do not containthe muscular layers or adventitia, and they only involve the submucosaand mucosa. Diverticula can occur anywhere in the gastrointestinal tractbut are usually observed in the colon. The sigmoid colon has the highestintraluminal pressures and is most commonly affected.

Diverticulae found in the left colon (predominantly in the sigmoid) areusually false diverticula, and they are commonly found in Westernpopulations. Right-sided and cecal diverticulae, however, are morecommonly true diverticulae, and they are usually found in people ofAsian descent. Cecal diverticulae are generally rare compared to thosefound in the left colon.

Diverticulosis is defined as the condition of having uninflameddiverticula; it occurs commonly with increasing age. The cause ofdiverticulosis is not yet conclusive, but it appears to be associatedwith a low-fiber diet, constipation, and obesity.

Diverticulitis is defined as an inflammation of one or more diverticula.Its pathogenesis remains unclear. Fecal material or undigested foodparticles may collect in a diverticulum, causing obstruction. Thisobstruction may result in distension of the diverticula secondary tomucous secretion and overgrowth of normal colonic bacteria. Vascularcompromise and subsequent microperforation or macroperforation thenensue. Alternatively, some believe that increased intraluminal pressureor inspissated food particles cause erosion of the diverticular wall,resulting in inflammation, focal necrosis, and perforation. The diseaseis frequently mild when pericolic fat and mesentery wall off a smallperforation. However, larger perforations and more extensive diseaselead to abscess formation and, rarely, intestinal rupture orperitonitis.

Fistula formation is a complication of diverticulitis. Fistulas toadjacent organs and the skin may develop, especially in the presence ofan abscess. In men, colovesicular fistulas are the most common. Inwomen, the uterus is interposed between the colon and the bladder, andthis complication is only seen following a hysterectomy. The uterusprecludes fistula formation from the sigmoid colon to the urinarybladder. However, colovaginal and colocutaneous fistulas can form butare uncommon.

Recurrent attacks of diverticulitis can result in the formation of scartissue, leading to narrowing and obstruction of the colonic lumen. Asused herein, recurrent diverticulitis, relapsing diverticulitits, orchronic diverticulitits are used interchangeably.

Many chronic diseases and disorders of the GI tract have chronicinfection/infestation as their underlying pathological conditions (e.g.,recurrent diverticulitis). In one aspect, the present disclosureincludes and relates to the use of a fecal microbiota, one or moremicrobial species therefrom, an active fragment or component therefromfor the treatment and/or prophylaxis of various disease states (e.g.,recurrent diverticulitis) related to the presence of ‘abnormal’microflora in the GI tract. An active fragment of a bacterium can be anyactive molecule isolated from such bacteria by any known method forpreparing/identifying active fragments of bacteria and proteins secretedfrom bacteria. Such methods include but are not limited to thefollowing: sonication, osmotic shock, detergent lysis, high pressure,transfer appropriate DNA to other organisms, such as bacteria, plant oranimal that is then used as a feed additive as described previously. Inone aspect, an active fragment or component of a bacterium is selectedfrom the group consisting of a mycolate or a derivative thereof, apolysaccharide, a lipoglycan, a small peptide, a thiopeptide, a protein,a nucleic acid molecule, a metabolite, a cell wall component, or anycombination thereof. In one aspect, an active fragment is a protein or asecretion. In another aspect, an active fragment is a secreted protein.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering to the subject a pharmaceutically active dose ofa therapeutic composition comprising live non-pathogenic fecal bacteria.In another aspect, this disclosure provides use of a compositioncomprising live non-pathogenic fecal bacteria in the manufacture of amedication for the treatment of recurrent diverticulitis.

In one aspect, a method provided here is for treating a form ofdiverticulitis selected from the group consisting of acutediverticulitis and recurrent diverticulitis. In one aspect, atherapeutic composition comprises an isolated or purified population oflive non-pathogenic fecal bacteria. In one aspect, a therapeuticcomposition comprises a non-selected fecal microbiota. In anotheraspect, a therapeutic composition comprises a non-selected andsubstantially complete fecal microbiota. In another aspect, atherapeutic composition comprises a full-spectrum fecal microbiota. Inone aspect, a method further comprises administering a 5-aminosalicylicacid agent, a corticosteroid, an immunosuppressant, or a combinationthereof. In another aspect, a method further comprises administering5-aminosalicylic acid or a derivative thereof, sulfasalazine or aderivative thereof, or a combination thereof.

In one aspect, the present disclosure provides a method which eliminatesor reduces one or more recurrent diverticulitis symptoms selected fromthe group consisting of left lower quadrant pain, change in bowelhabits, nausea, vomiting, constipation, diarrhea, flatulence, andbloating. In another aspect, the present disclosure provides a methodwhich eliminates, improves, relieves, or reduces one or more recurrentdiverticulitis symptoms selected from the group consisting of abscess,phlegmon, fistula, stricture, stenosis, obstruction, bleeding, andperforation.

In one aspect, a patient treated here stays on a high fiber diet. Inanother aspect, a patient treated here does not need to maintain a highfiber diet. In a further aspect, a patient treated here can achieve acure without a high fiber diet. In one aspect, a patient treated herestays on an anti-inflammatory agent or drug. In another aspect, apatient treated here is capable of discontinuing an anti-inflammatoryagent or drug. In a further aspect, a patient treated here achieves aremission or cure free of using any anti-inflammatory agent or drug.

In one aspect, a patient treated here stays on a clear liquid diet forat least 1, 2, 3, 4, 5, 6, or 7 days. In another aspect, a patienttreated here does not need to undergo a clear liquid diet. In a furtheraspect, a patient treated here can achieve a cure without a clear liquiddiet.

In one aspect, a patient treated here is pretreated with 7-10 days oforal broad-spectrum antimicrobial therapy. In one aspect, a single-agentantibiotic regimen is used. In another aspect, a multiple-agentantibiotic regimen is used. Exemplary antibiotic regimens include thefollowing: (a) ciprofloxacin and metronidazole; (b)trimethoprim-sulfamethoxazole and metronidazole; (c) moxifloxacin, (d)amoxicillin/clavulanic acid. Further exemplary antibiotics includepiperacillin/tazobactam, ampicillin/sulbactam, ticarcillin/clavulanicacid, imipenem, meropenem, tigecycline (when severe penicillin allergyis a concern). In another aspect, a multiple-drug regimen may consist ofmetronidazole and a third-generation cephalosporin or a fluoroquinolone,such as the following: Ceftriaxone, Cefotaxime, Ciprofloxacin, andLevofloxacin.

In one aspect, a patient subject to a treatment method described herecomprises one or more surgical indications selected from the groupconsisting of free-air perforation with fecal peritonitis, suppurativeperitonitis secondary to a ruptured abscess, uncontrolled sepsis,abdominal or pelvic abscess, fistula formation, inability to rule outcarcinoma, and intestinal obstruction.

In one aspect, a patient subject to a treatment method described heredoes not exhibit one or more surgical indications selected from thegroup consisting of free-air perforation with fecal peritonitis,suppurative peritonitis secondary to a ruptured abscess, uncontrolledsepsis, abdominal or pelvic abscess, fistula formation, inability torule out carcinoma, and intestinal obstruction.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering to the subject a pharmaceutically active dose ofa therapeutic composition comprising live non-pathogenic bacteria. Inone aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering daily or weekly to the subject apharmaceutically active dose of a therapeutic composition comprisinglive non-pathogenic fecal bacteria. In one aspect, a therapeuticcomposition is administered to an recurrent diverticulitis patient inneed thereof at least once daily or at least once weekly for at leasttwo consecutive days or weeks. In one aspect, a therapeutic compositionis administered at least once daily or at least once weekly for at least3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days orweeks. In another aspect, a therapeutic composition is administered atleast once daily or at least once weekly for at least 1, 2, 3, 4, 5, 6,7, 8, 9, 10, 11, or 12 consecutive weeks. In one aspect, a therapeuticcomposition is administered at least once daily or at least once weeklyfor at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or20 consecutive days or weeks. In another aspect, a therapeuticcomposition is administered at least once daily or at least once weeklyfor at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeksor months. In a further aspect, a therapeutic composition isadministered at least once for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 consecutive months or years, chronically for a subject'sentire life span, or an indefinite period of time.

In one aspect, a therapeutic composition is administered to an recurrentdiverticulitis patient in need thereof at least twice daily or at leasttwice weekly for at least two consecutive days or weeks. In one aspect,a therapeutic composition is administered at least twice daily or atleast twice weekly for at least 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,or 15 consecutive days or weeks. In another aspect, a therapeuticcomposition is administered at least twice daily or at least twiceweekly for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutiveweeks. In one aspect, a therapeutic composition is administered at leasttwice daily or at least twice weekly for at most 4, 5, 6, 7, 8, 9, 10,11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days or weeks. Inanother aspect, a therapeutic composition is administered at least twicedaily or at least twice weekly for at most 1, 2, 3, 4, 5, 6, 7, 8, 9,10, 11, or 12 consecutive weeks or months. In a further aspect, atherapeutic composition is administered at least twice for at least 1,2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years,chronically for a subject's entire life span, or an indefinite period oftime.

In one aspect, a therapeutic composition is administered to an recurrentdiverticulitis patient in need thereof at least three times daily or atleast three times weekly for at least two consecutive days or weeks. Inone aspect, a therapeutic composition is administered at least threetimes daily or at least three times weekly for at least 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, or 15 consecutive days or weeks. In anotheraspect, a therapeutic composition is administered at least three limesdaily or at least three times weekly for at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 consecutive weeks. In one aspect, a therapeuticcomposition is administered at least three times daily or at least threetimes weekly for at most 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16,17, 18, 19, or 20 consecutive days or weeks. In another aspect, atherapeutic composition is administered at least three times daily or atleast three times weekly for at most 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,or 12 consecutive weeks or months. In a further aspect, a therapeuticcomposition is administered at least three times for at least 1, 2, 3,4, 5, 6, 7, 8, 9, 10, 11, or 12 consecutive months or years, chronicallyfor a subject's entire life span, or an indefinite period of time.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises administering orally to the subject a pharmaceutically activedose of a therapeutic composition comprising live, non-pathogenic,synthetic bacterial mixture or live, non-pathogenic, purified orextracted, fecal microbiota, where the dose is administered at a dosingschedule of at least once or twice daily or at least once or twiceweekly for at least three consecutive days or weeks. In another aspect,a dose is administered at least once, twice, or three times daily or atleast once, twice, or three times daily for a period between 1 and 12weeks, between 2 and 12 weeks, between 3 and 12 weeks, between 4 and 12weeks, between 5 and 12 weeks, between 6 and 12 weeks, between 7 and 12weeks, between 8 and 12 weeks, between 9 and 12 weeks, between 10 and 12weeks, between 1 and 2 weeks, between 2 and 3 weeks, between 3 and 4weeks, between 4 and 5 weeks, between 5 and 6 weeks, between 6 and 7weeks, between 7 and 8 weeks, between 8 and 9 weeks, between 9 and 10weeks, or between 10 and 11 weeks.

In one aspect, the present disclosure provides a method for treatingrecurrent diverticulitis in a subject in need thereof, where the methodcomprises a first dosing schedule followed by a second dosing schedule.In one aspect, a first dosing schedule comprises a treatment orinduction dose. In one aspect, a first dosing schedule comprises acontinuous dosing schedule. In another aspect, a second dosing schedulecomprises a maintenance dose lower than or equal to a pharmaceuticallyactive dose of a first dosing schedule. In another aspect, a seconddosing schedule lasts for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36,48, 72, or 96 months. In one aspect, a second dosing schedule lastspermanently, for a treated subject's entire life span, or an indefiniteperiod of time. In one aspect, a second dosing schedule is a continuousdosing schedule. In another aspect, a second dosing schedule is anintermittent dosing schedule. In a further aspect, a second dosingschedule is an intermittent dosing schedule comprising a treatmentperiod of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 daysfollowed by a resting period of at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, 12, 13, or 14 days. In another aspect, a second dosing schedulecomprises administering a second dose (e.g., a maintenance dose) everyother day, every two days, or every 3, 4, 5, 6, 7, 8 days. In anotheraspect, a maintenance dose is administered for an extended period oftime with or without titration (or otherwise changing the dosage ordosing schedule). In one aspect, the interval between a first and asecond dosing schedule is at least about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,11, or 12 weeks. In another aspect, a second dosing schedule (e.g., amaintenance dose) comprises a dosage about 2, 5, 10, 50, 100, 200, 400,800, 1000, 5000 or more folds lower than the dosage used in a firstdosing schedule (e.g., an initial treatment dose). In another aspect, asecond dosing schedule (e.g., a maintenance dosing schedule) has anequal or lower dosing frequency than a first dosing schedule (e.g., aninitial treatment dosing schedule). In another aspect, a second dosingschedule (e.g., a maintenance dosing schedule) has a higher dosinginterval than a first dosing schedule (e.g., an initial treatment dosingschedule).

In one aspect, a first or second dosing schedule used in a method can beonce-a-week, twice-a-week, or thrice-a-week. The term “once-a-week”means that a dose is administered once in a week, preferably on the sameday of each week. “Twice-a-week” means that a dose is administered twotimes in a week, preferably on the same two days of each weekly period.“Thrice-a-week” means that a dose is administered three times in a week,preferably on the same three days of each weekly period.

In one aspect, a subject being treated is a subject already withrecurrent diverticulitis. Administration of a disclosed therapeuticcomposition to clinically, asymptomatic human subject who is geneticallypredisposed or prone to recurrent diverticulitis is also useful inpreventing the onset of clinical symptoms of recurrent diverticulitis. Ahuman subject genetically predisposed or prone to recurrentdiverticulitis can be a human subject having a close family member orrelative exhibiting or having suffered recurrent diverticulitis. Inanother aspect, a subject being treated is a subject in which recurrentdiverticulitis is to be prevented. In another aspect, a subject beingtreated is predisposed or susceptible to recurrent diverticulitis. Inanother aspect, a subject being treated is a subject diagnosed as havingrecurrent diverticulitis. In one aspect, a subject being treated is apatient in need of diverticulitis treatment. In another aspect, apatient being treated is immunocompromised. In another aspect, a patientbeing treated has both recurrent diverticulitis and IBD, IBS, or a C.diff infection.

In one aspect, a subject being treated has a stage I, stage II, stageIII, or stage IV diverticulitis. In one aspect, the clinical staging ofdiverticulitis follows a modified Hinchey classification. Stage I isdefined by the presence of a pericolic abscess. Stage II is defined bydistant abscesses susceptible to percutaneous drainage. Stage III isdefined by complex abscesses associated with a possible fistula. StageIV is defined by fecal peritonitis. In another aspect, the clinicalstaging of diverticulitis follows Hinchey's classification as follows:Stage I: Diverticulitis with phlegmon or localized pericolic ormesenteric abscess; Stage II: Diverticulitis with walled-off pelvic,intra-abdominal, or retroperitoneal abscess; Stage III: Perforateddiverticulitis causing generalized purulent peritonitis; and Stage IV:Rupture of diverticula into the peritoneal cavity with fecalcontamination causing generalized fecal peritonitis.

In one aspect, a patient is subject to a treatment described here afterbeing diagnosed with diverticulitis via computed tomography (CT)scanning of the abdomen. In another aspect, a diverticulitis patienttreated here has a CT finding selected from the group consisting ofpericolic fat stranding due to inflammation, colonic diverticula, bowelwall thickening, soft-tissue inflammatory masses, phlegmon, andabscesses. In one aspect, a diverticulitis patient treated here withoutrequiring prior diagnosis via CT.

In one aspect, a subject being treated is a human patient. In oneaspect, a patient is a male patient. In one aspect, a patient is afemale patient. In one aspect, a patient is a premuature newborn. In oneaspect, a patient is a term newborn. In one aspect, a patient is aneonate. In one aspect, a patient is an infant. In one aspect, a patientis a toddler. In one aspect, a patient is a young child. In one aspect,a patient is a child. In one aspect, a patient is an adolescent. In oneaspect, a patient is a pediatric patient. In one aspect, a patient is ageriatric patient. In one aspect, a human patient is a child patientbelow about 18, 15, 12, 10, 8, 6, 4, 3, 2, or 1 year old. In anotheraspect, a human patient is an adult patient. In another aspect, a humanpatient is an elderly patient. In a further aspect, a human patient is apatient above about 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90,or 95 years old. In another aspect, a patient is about between 1 and 5,between 2 and 10, between 3 and 18, between 21 and 50, between 21 and40, between 21 and 30, between 50 and 90, between 60 and 90, between 70and 90, between 60 and 80, or between 65 and 75 years old. In oneaspect, a patient is a young old patient (65-74 years). In one aspect, apatient is a middle old patient (75-84 years). In one aspect, a patientis an old patient (>85 years).

In one aspect, a method comprises administering a therapeuticcomposition orally, by enema, or via rectal suppository. In one aspect,a therapeutic composition administered herein is formulated as anenteric coated (and/or acid-resistant) capsule or microcapsule, orformulated as part of or administered together with a food, a foodadditive, a dairy-based product, a soy-based product or a derivativethereof, a jelly, flavored liquid, ice block, ice-cream, or a yogurt. Inanother aspect, a therapeutic composition administered herein isformulated as an acid-resistant enteric coated capsule. A therapeuticcomposition can be provided as a powder for sale in combination with afood or drink. A food or drink can be a dairy-based product or asoy-based product. In another aspect, a food or food supplement containsenteric-coated and/or acid-resistant microcapsules containing atherapeutic composition.

In an aspect, a therapeutic composition comprises a liquid culture. Inanother aspect, a therapeutic composition is lyophilized, pulverized andpowdered. It may then be infused, dissolved such as in saline, as anenema. Alternatively the powder may be encapsulated as enteric-coatedand/or acid-resistant capsules for oral administration. These capsulesmay take the form of enteric-coated and/or acid-resistant microcapsules.A powder can preferably be provided in a palatable form forreconstitution for drinking or for reconstitution as a food additive. Ina further aspect, a food is yogurt. In one aspect, a powder may bereconstituted to be infused via naso-duodenal infusion.

In another aspect, a therapeutic composition administered herein is in aliquid, frozen, freeze-dried, spray-dried, lyophilized, or powder form.In a further aspect, a therapeutic composition administered herein isformulated as a delayed or gradual enteric release form.

In another aspect, a therapeutic composition administered hereincomprises an excipient, a saline, a buffer, a buffering agent, or afluid-glucose-cellobiose agar (RGCA) media. In another aspect, atherapeutic composition administered herein comprises a cryoprotectant.In one aspect, a cryoprotectant comprises polyethylene glycol, skimmilk, erythritol, arabitol, sorbitol, glucose, fructose, alanine,glycine, proline, sucrose, lactose, ribose, trehalose, dimethylsulfoxide (DMSO), glycerol, or a combination thereof.

In one aspect, a therapeutic composition administered herein furthercomprises an acid suppressant, an antacid, an H2 antagonist, a protonpump inhibitor or a combination thereof. In one aspect, a therapeuticcomposition administered herein substantially free of non-living matter.In another aspect, a therapeutic composition administered hereinsubstantially free of acellular material selected from the groupconsisting of residual fiber, DNA, viral coat material, and non-viablematerial.

In one aspect, a therapeutic composition also comprises or issupplemented with a prebiotic nutrient selected from the groupconsisting of polyols, fructooligosaccharides (FOSs), oligofructoses,inulins, galactooligosaccharides (GOSs), xylooligosaccharides (XOSs),polydextroses, monosaccharides, tagatose, and/or mannooligosaccharides.

In one aspect, a method further comprises pretreating a subject with anantibiotic composition prior to administering a therapeutic bacterial ormicrobiota composition. In one aspect, an antibiotic compositionadministered herein comprises an antibiotic selected from the groupconsisting of rifabutin, clarithromycin, clofazimine, vancomycin,rifampicin, nitroimidazole, chloramphenicol, and a combination thereof.In another aspect, an antibiotic composition administered hereincomprises an antibiotic selected from the group consisting of rifaximin,rifamycin derivative, rifampicin, rifabutin, rifapentine, rifalazil,bicozamycin, aminoglycoside, gentamycin, neomycin, streptomycin,paromomycin, verdamicin, mutamicin, sisomicin, netilmicin, retymicin,kanamycin, aztreonam, aztreonam macrolide, clarithromycin,dirithromycin, roxithromycin, telithromycin, azithromycin, bismuthsubsalicylate, vancomycin, streptomycin, fidaxomicin, amikacin,arbekacin, neomycin, netilmicin, paromomycin, rhodostreptomycin,tobramycin, apramycin, and a combination thereof. In a further aspect, amethod further comprises pretreating a subject with an anti-inflammatorydrug prior to administration of a therapeutic bacterial or microbiotacomposition.

In one aspect, a method achieves a remission, cure, response, orresolution rate of recurrent diverticulitis of at least about 10%, 15%,20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%,90%, 95%, 97%, or 99%. In one aspect, a treatment method described herereduces the recurrence frequency in a recurrent diverticulitis patientby at least 10%, 20%, 30%, 50%, 60%, 70%, 80%, or 90% in at least 10%,20%, 30%, 50%, 60%, 70%, 80%, or 90% patients compared to baseline(e.g., immediately prior to treatment).

In one aspect, every about 200 mg of a pharmaceutical compositioncomprises a pharmacologically active dose. In one aspect, every about75, 100, 125, 150, 175, 200, 250, 300, 350, 400, 450, 500, 750, 1000,1500, or 2000 mg of a pharmaceutical composition comprises apharmacologically active dose.

In one aspect, a pharmaceutically active or therapeutic effective dosecomprises at least about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or10¹³ cfu. In another aspect, a pharmaceutically active therapeuticeffective dose comprises at most about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰,10¹¹, 10 ¹², or 10¹³ cfu. In a further aspect, a pharmacologicallyactive therapeutic effective dose is selected from the group consistingof from 10⁸ cfu to 10¹⁴ cfu, from 10⁹ cfu to 10¹³ cfu, from 10¹⁰ cfu to10¹² cfu, from 10⁹ cfu to 10¹⁴ cfu, from 10⁹ cfu to 10¹² cfu, from 10⁹cfu to 10¹¹ cfu, from 10⁹ cfu to 10¹⁰ cfu, from 10¹⁰ cfu to 10¹⁴ cfu,from 10¹⁰ cfu to 10¹³ cfu, from 10¹¹ cfu to 10¹⁴ cfu, from 10¹¹ cfu to10¹³ cfu, from 10¹² cfu to 10¹⁴ cfu, and from 10¹³ cfu to 10¹⁴ cfu. Inone aspect, a pharmaceutical composition comprises the foregoingpharmaceutically active or therapeutic effective dose in a unit weightof about 0.2, 0.4, 0.6, 0.8 or 1.0 gram, or a unit volume of about 0.2,0.4, 0.6, 0.8 or 1.0 milliliter.

In one aspect, a pharmaceutically active or therapeutic effective dosecomprises at least about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or10¹³ cells or spores. In another aspect, a pharmaceutically active ortherapeutic effective dose comprises at most about 10⁵, 10⁶, 10⁷, 10⁸,10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³ total cells or spores. In a furtheraspect, a pharmacologically active or therapeutic effective dose isselected from the group consisting of from 10⁸ to 10¹⁴, from 10⁹ to10¹³, from 10¹⁰ to 10¹², from 10⁹ to 10¹⁴, from 10⁹ to 10¹², from 10⁹ to10¹¹, from 10⁹ to 10¹⁰ from 10¹⁰ to 10¹⁴, from 10¹⁰ to 10¹³ from 10¹¹ to10¹⁴, from 10¹¹ to 10¹³, from 10¹² to 10¹⁴, and from 10¹³ to 10¹⁴ cellsor spores. In an aspect, the pharmaceutically active or therapeuticeffective dose cell count is directed to live cells. In one aspect, apharmaceutical composition comprises the foregoing pharmaceuticallyactive or therapeutic effective dose in a unit weight of about 0.2, 0.4,0.6, 0.8 or 1.0 gram, or a unit volume of about 0.2, 0.4, 0.6, 0.8 or1.0 milliliter.

In one aspect, a therapeutic composition administered herein comprisesfecal bacteria. In one aspect, a therapeutic composition administeredherein comprises one or more, two or more, three or more, four or more,or five or more isolated, purified, or cultured microorganisms selectedfrom the group consisting of Clostridium, Bacillus, Collinsella,Bacteroides, Eubacterium, Fusobacterium, Propionibacterium,Lactobacillus, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas,Peptostreptococcus, Bifidobacterium, Coprococcus, Dorea, and Monilia.

In one aspect, a therapeutic composition administered herein comprisesat least one, at least two, at least three, at least four, at leastfive, at least six, or at least seven fecal microorganisms selected fromthe group consisting of a Bacteroides fragilis ssp. vulgatus,Collinsella aerofaciens, Bacteroides fragilis ssp. thetaiotaomicron,Peptostreptococcus productus II, Parabacteroides distasonis,Fusobacterium prausnitzli, Coprococcus eutactus, Collinsella aerofaciensIII, Peptostreptococcus productus I, Ruminococcus bromii,Bifidobacterium adolescentis, Geminiger formicilis, Bifidobacteriumlongum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale,Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum,Bacteroides fragilis ssp. A, Eubacterium biforme, Bifidobacteriuminfantis, Eubacterium rectale III-F, Coprococcus comes,Pseudoflavonifractor capillosus, Ruminococcus albus, Doreaformicigenerans, Eubacterium hallii, Eubacterium ventriosum I,Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale,Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus,Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacteriumventriosum, Bacteroides fragilis ssp. fragilis, Bacteroides AR,Coprococcus catus, Aerostipes hadrus, Eubacterium cylindroides,Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis,Peptostreptococcus BL, Eubacterium limosum, Tissirella praeacuta,Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme,Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes,Ruminococcus flavefaciens, Ruminococcus AT, Peptococcus AU-1,Bacteroides fragilis ssp. ovatus, -ssp. d, -ssp. f; Bacteroides L-1,L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichiacoli, Gemella morbillorum, Finegoldia magnus, Peptococcus G, -AU-2;Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus COGemmiger X, Coprococcus BH, —CC; Eubacterium tenue, Eubacterium ramulus,Bacteroides clostridiiformis ssp. clostridliformis, Bacteroidescoagulans, Prevotella oralis, Prevotella ruminicola, Odoribactersplanchnicus, Desuifomonas pigra, Lactobacillus G, Succinivibrio A, anda combination thereof.

In one aspect, a therapeutic composition administered herein comprisesno viable Bacteroides, Fusobacterium, Propionibacterium, Lactobacillus,Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas,Peptostreptococcus, Bifidobacterium, Monilia, or any combinationthereof. In another aspect, a therapeutic composition administeredherein comprises no viable Bacteroides fragilis ssp. vulgatus,Collinsella aerofaciens, Bacteroides fragilis ssp. thetaiotaomicron,Peptostreptococcus productus II, Parabacteroides distasonis,Fusobacterium prausnitzii, Coprococcus eutactus, Collinsella aerofaciensPeptostreptococcus productus T, Ruminococcus bromii, Bifidobacteriumadolescentis, Gemmiger formicilis, Bifidobacterium longum, Eubacteriumsiraeum, Ruminococcus torques, Eubacterium rectale, Eubacterium eligens,Bacteroides eggerthii, Clostridium leptum, Bacteroides fragilis ssp. A,Eubacterium biforme, Bifidobacterium infantis, Eubacterium rectaleIII-F, Coprococcus comes, Pseudoflavonifractor capillosus, Ruminococcusalbus, Dorea formicigenerans, Eubacterium hallii, Eubacterium ventriosumI, Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale,Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus,Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacteriumventriosum, Bacteroides fragilis ssp. fragilis, Bacteroides AR,Coprococcus catus, Aerostipes hadrus, Eubacterium cylindroides,Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis,Peptostreptococcus BL, Eubacterium limosum, Tissirella praeacuta,Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme,Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes,Ruminococcus flavefaciens, Ruminococcus AT, Peptococcus AU-1,Bacteroides fragilis ssp. ovatus, -ssp. d, -ssp. f; Bacteroides L-1,L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichiacoli, Gemella morbillorum, Finegoldia magnus, Peptococcus G, -AU-2;Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus COGemmiger X, Coprococcus BH, —CC; Eubacterium tenue, Eubacterium ramulus,Bacteroides clostridiiformis ssp. clostridliformis Bacteroidescoagulans, Prevotella oralis, Prevotella ruminicola, Odoribactersplanchnicus, Desuifomonas pigra, Lactobacillus G, Succinivibrio A, or acombination thereof.

In one aspect, a therapeutic composition administered herein comprises afecal microbiota. In another aspect, the preparation of a fecalmicrobiota used herein involves a treatment selected from the groupconsisting of ethanol treatment, detergent treatment, heat treatment,irradiation, and sonication. In another aspect, the preparation of afecal microbiota used herein involves no treatment selected from thegroup consisting of ethanol treatment, detergent treatment, heattreatment, irradiation, and sonication. In one aspect, the preparationof a fecal microbiota used herein involves a separation step selectedfrom the group consisting of density gradients, filtration (e.g.,sieves, nylon mesh), and chromatography. In another aspect, thepreparation of a fecal microbiota used herein involves no separationstep selected from the group consisting of density gradients, filtration(e.g., sieves, nylon mesh), and chromatography. In another aspect, afecal microbiota used herein comprises a donor's entire fecalmicrobiota. In another aspect, a therapeutic composition administeredherein comprises a fecal microbiota substantially free of eukaryoticcells from the fecal microbiota's donor.

In another aspect, a therapeutic composition administered hereincomprises a fecal microbiota further supplemented, spiked, or enhancedwith a fecal microorganism. In one aspect, a fecal microbiota issupplemented with a non-pathogenic (or with attenuated pathogenicity)bacterium of Clostridium, Collinsella, Dorea, Ruminococcus, Coprococcus,Prevotella, Veillonella, Bacteroides, Baccillus, or a combinationthereof. In another aspect, a therapeutic composition administeredherein comprises a fecal microbiota further supplemented, spiked, orenhanced with a species of Veillonellaceae, Firmicutes,Gammaproteobacteria, Bacteroidetes, or a combination thereof. In anotheraspect, a therapeutic composition administered herein comprises a fecalmicrobiota further supplemented with fecal bacterial spores. In oneaspect, fecal bacterial spores are Clostridium spores, Bacillus spores,or both.

In an aspect, a therapeutic composition comprises a fecal microbiotafrom a subject selected from the group consisting of a human, a bovine,a dairy calf, a ruminant, an ovine, a caprine, or a cervine. In anotheraspect, a therapeutic composition can be administered to a subjectselected from the group consisting of a human, a bovine, a dairy calf, aruminant, an ovine, a caprine, or a cervine. In an aspect, a therapeuticcomposition is substantially or nearly odourless.

In an aspect, a therapeutic composition provided or administered hereincomprises a fecal microbiota comprising a Shannon Diversity Index ofgreater than or equal to 0.3, greater than or equal to 0.4, greater thanor equal to 0.5, greater than or equal to 0.6, greater than or equal to0.7, greater than or equal to 0.8, greater than or equal to 0.9, greaterthan or equal to 1.0, greater than or equal to 1.1, greater than orequal to 1.2, greater than or equal to 1.3, greater than or equal to1.4, greater than or equal to 1.5, greater than or equal to 1.6, greaterthan or equal to 1.7, greater than or equal to 1.8, greater than orequal to 1.9, greater than or equal to 2.0, greater than or equal to2.1, greater than or equal to 2.2, greater than or equal to 2.3, greaterthan or equal to 2.4, greater than or equal to 2.5, greater than orequal to 3.0, greater than or equal to 3.1, greater than or equal to3.2, greater than or equal to 3.3, greater than or equal to 3.4, greaterthan or equal to 3.5, greater than or equal to 3.6, greater than orequal to 3.7, greater than or equal to 3.8, greater than or equal to3.9, greater than or equal to 4.0, greater than or equal to 4.1, greaterthan or equal to 4.2, greater than or equal to 4.3, greater than orequal to 4.4, greater than or equal to 4.5, or greater than or equal to5.0. In another aspect, a therapeutic composition comprises fecalmicrobiota comprising a Shannon Diversity index of between 0.1 and 3.0,between 0.1 and 2.5, between 0.1 and 2.4, between 0.1 and 2.3, between0.1 and 2.2, between 0.1 and 2.1, between 0.1 and 2.0, between 0.4 and2.5, between 0.4 and 3.0, between 0.5 and 5.0, between 0.7 and 5.0,between 0.9 and 5.0, between 1.1 and 5.0, between 1.3 and 5.0, between1.5 and 5.0, between 1.7 and 5.0, between 1.9 and 5.0, between 2.1 and5.0, between 2.3 and 5.0, between 2.5 and 5.0, between 2.7 and 5.0,between 2.9 and 5.0, between 3.1 and 5.0, between 3.3 and 5.0, between3.5 and 5.0, between 3.7 and 5.0, between 31.9 and 5.0, or between 4.1and 5.0. In one aspect, a Shannon Diversity Index is calculated at thephylum level. In another aspect, a Shannon Diversity Index is calculatedat the family level. In one aspect, a Shannon Diversity Index iscalculated at the genus level. In another aspect, a Shannon DiversityIndex is calculated at the species level. In a further aspect, atherapeutic composition comprises a preparation of flora in proportionalcontent that resembles a normal healthy human fecal flora.

In a further aspect, a therapeutic composition comprises fecal bacteriafrom at least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 different families. In anaspect, a therapeutic composition provided or administered hereincomprises a fecal microbiota comprising no greater than 0.05%, 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%,7%, 8%, 9%, or 10% weight non-living material/weight biologicalmaterial. In another aspect, a therapeutic composition provided oradministered herein comprises a fecal microbiota comprising no greaterthan 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%,85%, 90%, or 95% weight non-living material/weight biological material.In another aspect, a therapeutic composition provided or administeredherein comprises, consists of, or consists essentially of, particles ofnon-living material and/or particles of biological material of a fecalsample that passes through a sieve, a column, or a similar filteringdevice having a sieve, exclusion, or particle filter size of 2.0 mm, 1.0mm, 0.33 mm, 0.5 mm, 0.25 mm, 0.212 mm, 0.180 mm, 0.150 mm, 0.125 mm,0.106 mm, 0.090 mm, 0.075 mm, 0.063 mm, 0.053 mm, 0.045 mm, 0.038 mm,0.032 mm, 0.025 mm, 0.020 mm, 0.01 mm, or 0.2 mm. “Non-living material”does not include an excipient, e.g., a pharmaceutically inactivesubstance, such as a cryoprotectant, added to a processed fecalmaterial. “Biological material” refers to the living material in fecalmaterial, and includes microbes including prokaryotic cells, such asbacteria and archaea (e.g., living prokaryotic cells and spores that cansporulate to become living prokaryotic cells), eukaryotic cells such asprotozoa and fungi, and viruses. In one aspect, “biological material”refers to the living material, e.g., the microbes, eukaryotic cells, andviruses, which are present in the colon of a normal healthy human. In anaspect, a therapeutic composition provided or administered hereincomprises an extract of human feces where the composition issubstantially odorless. In an aspect, a therapeutic composition providedor administered herein comprises fecal material or a fecal floralpreparation in a lyophilized, crude, semi-purified or purifiedformulation.

In an aspect, a fecal microbiota in a therapeutic composition compriseshighly refined or purified fecal flora, e.g., substantially free ofnon-floral fecal material. In an aspect, a fecal microbiota can befurther processed, e.g., to undergo microfiltration before, after, orbefore and after sieving. In another aspect, a highly purified fecalmicrobiota product is ultra-filtrated to remove large molecules butretain the therapeutic microflora, e.g., bacteria.

In another aspect, a fecal microbiota in a therapeutic composition usedherein comprises or consists essentially of a substantially isolated ora purified fecal flora or entire (or substantially entire) microbiotathat is (or comprises) an isolate of fecal flora that is at least about90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99%, 99.5%, 99.6%, 99.7%,99.8% or 99.9% isolated or pure, or having no more than about 0.1%,0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9% or 1.0% or more non-fecalfloral material; or, a substantially isolated, purified, orsubstantially entire microbiota as described in Sadowsky et al., WO2012/122478 A1, or as described in Borody et al., WO 2012/016287 A2.

In an aspect, a fecal microbiota in a therapeutic composition comprisesa donor's substantially entire or non-selected fecal microbiota,reconstituted fecal material, or synthetic fecal material. In anotheraspect, the fecal microbiota in a therapeutic composition comprises noantibiotic resistant population. In another aspect, a therapeuticcomposition comprises a fecal microbiota and is largely free ofextraneous matter (e.g., non-living matter including acellular mattersuch as residual fiber, DNA, RNA, viral coat material, non-viablematerial; and living matter such as eukaryotic cells from the fecalmatter's donor).

In an aspect, a fecal microbiota in a therapeutic composition usedherein is derived from disease-screened fresh homologous feces orequivalent freeze-dried and reconstituted feces. In an aspect, a freshhomologous feces does not include an antibiotic resistant population. Inanother aspect, a fecal microbiota in a therapeutic composition isderived from a synthetic fecal composition. In an aspect, a syntheticfecal composition comprises a preparation of viable flora whichpreferably in proportional content, resembles normal healthy human fecalflora which does not include antibiotic resistant populations. Suitablemicroorganisms may be selected from the following: Bacteroides,Eubacterium, Fusobacterium, Propionibacterium, Lactobacillus,Ruminococcus. Escherichia coli, Gemmiger, Clostridium, Desulfomonas,Peptostreptococcus, Bifidobacterium, Collinsella, Coprococcus, Dorea,and Ruminococcus.

In an aspect, a therapeutic composition used in a treatment disclosedherein comprises a sterile fecal filtrate or a non-cellular fecalfiltrate. In one aspect, a sterile fecal filtrate originates from adonor stool. In another aspect, a sterile fecal filtrate originates fromcultured microorganisms. In another aspect, a sterile fecal filtratecomprises a non-cellular non-particulate fecal component. In one aspect,a sterile fecal filtrate is made as described in WO2014/078911,published May 30, 2014. In another aspect, a sterile fecal filtrate ismade as described in Ott et al., Gastroenterology 152:799-911(2017).

In one aspect, a fecal filtrate comprises secreted, execreted orotherwise liquid components or a microbiota, e.g., biologically activemolecules (BAMs), which can be antibiotics or anti-inflammatories, arepreserved, retained or reconstituted in a flora extract.

In one aspect, an exemplary therapeutic composition comprises startingmaterial from a donor from a defined donor pool, where this donorcontributes a stool that is centrifuged, then filtered with veryhigh-level filtration using e.g., either metal sieving or Milliporefilters, or equivalent, to ultimately permit only cells of bacterialorigin to remain, e.g., often less than about 5 micrometres diameter.After the initial centrifugation, the solid material is separated fromthe liquid, and the solid is then filtered in progressively reducingsize filters and tangential filters, e.g., using a Millipore filtration,and optionally, also comprising use of nano-membrane filtering. Thefiltering can also be done by sieves as described in WO 2012/122478, butin contrast using sieves that are smaller than 0.0120 mm, down to about0.0110 mm, which ultimately result in having only bacterial cellspresent.

The supernatant separated during centrifugation is now taken andfiltered progressively in a filtering, e.g., a Millipore filtering orequivalent systems, to end up with liquid which is finely filteredthrough an about 0.22 micron filter. This removes all particulate matterincluding all living matter, including bacteria and viruses. The productthen is sterile, but the aim is to remove the bacteria but to keep theirsecretions, especially antimicrobial bacteriocins, bacteria-derivedcytokine-like products and all accompanying Biologically ActiveMolecules (BAMs), including: thuricin (which is secreted by bacilli indonor stools), bacteriocins (including colicin, troudulixine orputaindicine, or microcin or subtilosin A), lanbiotics (including nisin,subtilin, epidermin, mutacin, mersacidin, actagardine, cinnamycin),lacticins and other antimicrobial or anti-inflammatory compounds.

In one aspect, a therapeutic composition used here comprises areconstituted fecal flora consisting essentially of a combination of apurified fecal microbiota and a non-cellular fecal filtrate. In anotheraspect, a therapeutic composition used here comprises a purified fecalmicrobiota supplemented with one or more non-cellular non-particulatefecal components. In one aspect, a therapeutic composition used herecomprises one or more non-cellular non-particulate fecal components. Inone aspect, one or more non-cellular non-particulate fecal componentscomprise synthetic molecules, biologically active molecules produced bya fecal microorganism, or both. In another aspect, one or morenon-cellular non-particulate fecal components comprise biologicallyactive proteins or peptides, micronutrients, fats, sugars, smallcarbohydrates, trace elements, mineral salts, ash, mucous, amino acids,nutrients, vitamins, minerals, or any combination thereof. In oneaspect, one or more non-cellular non-particulate fecal componentscomprise one or more biologically active molecules selected from thegroup consisting of bacteriocin, lanbiotic, and lacticin. In anotheraspect, one or more non-cellular non-particulate fecal componentscomprise one or more bacteriocins selected from the group consisting ofcolicin, troudulixine, putaindicine, microcin, and subtilosin A. In oneaspect, one or more non-cellular non-particulate fecal componentscomprise one or more lanbiotics selected from the group consisting ofthuricin, nisin, subtilin, epidermin, mutacin, mersacidin, actagardine,and cinnamycin. In another aspect, one or more non-cellularnon-particulate fecal components comprise an anti-spore compound, anantimicrobial compound, an anti-inflammatory compound, or anycombination thereof. In a further aspect, one or more non-cellularnon-particulate fecal components comprise an interleukin, a cytokine, aleukotriene, an eicosanoid, or any combination thereof.

In another aspect, a treatment method provided here comprises the use ofboth fecal bacterial cells, e.g., a partial or a complete representationof the human GI microbiota, and an isolated, processed, filtered,concentrated, reconstituted and/or artificial liquid component (e.g.,fecal filtrate) of the flora (the microbiota) which comprises, amongothers ingredients, bacterial secretory products such as e.g.,bacteriocins (proteinaceous toxins produced by bacteria, includingcolicin, troudulixine or putaindicine, or microcin or subtilosin A),lanbiotics (a class of peptide antibiotics that contain a characteristicpolycyclic thioether amino acid lanthionine or methyllanthionine, andunsaturated amino acids dehydroalanine and 2-aminoisobutyric acid; whichinclude thuricin (which is secreted by bacilli in donor stools), nisin,subtilin, epidermin, mutacin, mersacidin, actagardine, cinnamycin), alacticin (a family of pore-forming peptidic toxins) and otherantimicrobial or anti-inflammatory compounds and/or additionalbiologically active molecules (BAMs) produced by bacteria or othermicroorganisms of the microbiota, and/or which are found in the “liquidcomponent” of a microbiota.

In one aspect, a fecal bacteria-based therapeutic composition is usedconcurrently with a fecal non-cellular filtrate-based therapeuticcomposition. In another aspect, a patient is treated with a first fecalnon-cellular filtrate-based therapeutic composition before being given asecond fecal bacteria-based therapeutic composition, or vice versa. In afurther aspect, a treatment method comprises three steps: first,antibiotic pre-treatment to non-selectively remove infectiouspathogen(s); second, a fecal non-cellular filtrate-based treatment stepto further suppress selected infectious pathogen(s); and third, givingthe patient a fecal bacteria-based therapeutic composition tore-establish a functional intestinal microbiome.

In an aspect, a therapeutic composition is combined with other adjuvantssuch as antacids to dampen bacterial inactivation in the stomach. (e.g.,Mylanta, Mucaine, Gastrogel). In another aspect, acid secretion in thestomach could also be pharmacologically suppressed using H2-antagonistsor proton pump inhibitors. An example H2-antagonist is ranitidine. Anexample proton pump inhibitor is omeprazole. In one aspect, an acidsuppressant is administered prior to administering, or inco-administration with, a therapeutic composition.

In an aspect, a therapeutic composition is in the form of: an enemacomposition which can be reconstituted with an appropriate diluent;enteric-coated capsules; enteric-coated microcapsules; acid-resistanttablet; acid-resistant capsules; acid-resistant microcapsules; powderfor reconstitution with an appropriate diluent for naso-enteric infusionor colonoscopic infusion; powder for reconstitution with appropriatediluent, flavoring and gastric acid suppression agent for oralingestion; powder for reconstitution with food or drink; or food or foodsupplement comprising enteric-coated and/or acid-resistant microcapsulesof the composition, powder, jelly, or liquid.

In an aspect, a treatment method effects a cure, reduction of thesymptoms, or a percentage reduction of symptoms of recurrentdiverticulitis. The change of flora is preferably as “near-complete” aspossible and the flora is replaced by viable organisms which will crowdout any remaining, original flora. Typically the change in enteric floracomprises introduction of an array of predetermined flora into thegastro-intestinal system, and thus in a preferred form the method oftreatment comprises substantially or completely displacing pathogenicenteric flora in patients requiring such treatment.

In another aspect, a therapeutic composition can be provided togetherwith a pharmaceutically acceptable carrier. As used herein, a“pharmaceutically acceptable carrier” refers to a non-toxic solvent,dispersant, excipient, adjuvant, or other material which is mixed with alive bacterium in order to permit the formation of a pharmaceuticalcomposition, e.g., a dosage form capable of administration to thepatient. A pharmaceutically acceptable carrier can be liquid (e.g.,saline), gel or solid form of diluents, adjuvant, excipients or an acidresistant encapsulated ingredient. Suitable diluents and excipientsinclude pharmaceutical grades of physiological saline, dextrose,glycerol, mannitol, lactose, starch, magnesium stearate, sodiumsaccharin, cellulose, magnesium carbonate, and the like, andcombinations thereof. In another aspect, a therapeutic composition maycontain auxiliary substances such as wetting or emulsifying agents,stabilizing or pH buffering agents. In an aspect, a therapeuticcomposition contains about 1%-5%, 5%-10%, 10%-15%, 15-20%, 20%-25%,25-30%, 30-35%, 40-45%, 50%-55%, 1%-95%, 2%-95%, 5%-95%, 10%-95%,15%-95%, 20%-95%, 25%-95%, 30%-95%, 35%-95%, 40%-95%, 45%-95%, 50%-95%,55%-95%, 60%-95%, 65%-95%, 70%-95%, 45%-95%, 80%-95%, or 85%-95% ofactive ingredient. In an aspect, a therapeutic composition containsabout 2%-70%, 5%-60%, 10%-50%, 15%-40%, 20%-30%, 25%-60%, 30%-60%, or35%-60% of active ingredient.

In an aspect, a therapeutic composition can be incorporated intotablets, drenches, boluses, capsules or premixes. Formulation of theseactive ingredients into such dosage forms can be accomplished by meansof methods well known in the pharmaceutical formulation arts. See, e.g.,U.S. Pat. No. 4,394,377. Filling gelatin capsules with any desired formof the active ingredients readily produces capsules. If desired, thesematerials can be diluted with an inert powdered diluent, such as sugar,starch, powdered milk, purified crystalline cellulose, or the like toincrease the volume for convenience of filling capsules.

In an aspect, conventional formulation processes can be used to preparetablets containing a therapeutic composition. In addition to the activeingredients, tablets may contain a base, a disintegrator, an absorbent,a binder, and a lubricant. Typical bases include lactose, sugar, sodiumchloride, starch and mannitol. Starch is also a good disintegrator as isalginic acid. Surface-active agents such as sodium lauryl sulfate anddioctyl sodium sulphosuccinate are also sometimes used. Commonly usedabsorbents include starch and lactose. Magnesium carbonate is alsouseful for oily substances. As a binder there can be used, for example,gelatin, gums, starch, dextrin, polyvinyl pyrrolidone and variouscellulose derivatives. Among the commonly used lubricants are magnesiumstearate, talc, paraffin wax, various metallic soaps, and polyethyleneglycol.

In an aspect, for preparing solid compositions such as tablets, anactive ingredient is mixed with a pharmaceutical carrier, e.g.,conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate or gums, or other pharmaceutical diluents, e.g. water, to forma solid preformulation composition containing a homogeneous mixture of acomposition of the present invention. When referring to thesepreformulation compositions as homogeneous, it is meant that the activeingredient is dispersed evenly throughout the composition so that thecomposition may be readily subdivided into equally effective unit dosageforms such as tablets, pills and capsules. This solid preformulationcomposition is then subdivided into unit dosage forms of the typedescribed above containing a desired amount of an active ingredient(e.g., at least about 10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³cfu or total cell count). A therapeutic composition used herein can beflavored.

In an aspect, a therapeutic composition can be a tablet or a pill. Inone aspect, a tablet or a pill can be coated or otherwise compounded toprovide a dosage form affording the advantage of prolonged action. Forexample, a tablet or pill can comprise an inner dosage and an outerdosage component, the latter being in the form of an envelope over theformer. The two components can be separated by an enteric layer whichserves to resist disintegration in the stomach and permits the innercomponent to pass intact into the duodenum or to be delayed in release.A variety of materials can be used for such enteric layers or coatings,such materials including a number of polymeric acids and mixtures ofpolymeric acids with such materials as shellac, cetyl alcohol andcellulose acetate.

In an aspect, a therapeutic composition can be a drench. In one aspect,a drench is prepared by choosing a saline-suspended form of atherapeutic composition. A water-soluble form of one ingredient can beused in conjunction with a water-insoluble form of the other bypreparing a suspension of one with an aqueous solution of the other.Water-insoluble forms of either active ingredient may be prepared as asuspension or in some physiologically acceptable solvent such aspolyethylene glycol. Suspensions of water-insoluble forms of eitheractive ingredient can be prepared in oils such as peanut, corn, sesameoil or the like; in a glycol such as propylene glycol or a polyethyleneglycol; or in water depending on the solubility of a particular activeingredient. Suitable physiologically acceptable adjuvants may benecessary in order to keep the active ingredients suspended. Adjuvantscan include and be chosen from among the thickeners, such ascarboxymethylcellulose, polyvinyl pyrrolidone, gelatin and thealginates. Surfactants generally will serve to suspend the activeingredients, particularly the fat-soluble propionate-enhancingcompounds. Most useful for making suspensions in liquid nonsolvents arealkylphenol polyethylene oxide adducts, naphthalenesulfonates,alkylbenzene-sulfonates, and the polyoxyethylene sorbitan esters. Inaddition many substances, which affect the hydrophilicity, density andsurface tension of the liquid, can assist in making suspensions inindividual cases. For example, silicone anti-foams, glycols, sorbitol,and sugars can be useful suspending agents.

In an aspect, a therapeutic composition comprises non-pathogenic sporesof one or more, two or more, three or more, or four or more Clostridiumspecies selected from the group consisting of Clostridium absonum,Clostridium argentinense, Clostridium baratii, Clostridium botulinum,Clostridium cadaveris, Clostridium carnis, Clostridium celatum,Clostridium chauvoei, Clostridium clostridioforme, Clostridiumcochlearium, Clostridium fallax, Clostridium felsineum, Clostridiumghonii, Clostridium glycolicum, Clostridium haemolyticum, Clostridiumhastiforme, Clostridium histolyticum, Clostridium indolis, Clostridiumirregulare, Clostridium limosum, Clostridium malenominatum, Clostridiumnovyi, Clostridium oroticum, Clostridium paraputrificum, Clostridiumperfringens, Clostridium piliforme, Clostridium putrefaciens,Clostridium putrificum, Clostridium sardiniense, Clostridiumsartagoforme, Clostridium scindens, Clostridium septicum, Clostridiumsordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridiumsporogenes, Clostridium subterminale, Clostridium symbiosum, Clostridiumtertium, Clostridium tetani, Clostridium welchii, and Clostridiumvillosum.

In an aspect, a therapeutic composition comprises purified, isolated, orcultured viable non-pathogenic Clostridium and a plurality of purified,isolated, or cultured viable non-pathogenic microorganisms from one ormore genera selected from the group consisting of Coprococcus, Dorea,Eubacterium, and Ruminococcus. In another aspect, a therapeuticcomposition comprises a plurality of purified, isolated, or culturedviable non-pathogenic microorganisms from one or more genera selectedfrom the group consisting of Clostridium, Collinsella, Coprococcus,Dorea, Eubacterium, and Ruminococcus.

In an aspect, a therapeutic composition comprises two or more generaselected from the group consisting of Collinsella, Coprococcus, Dorea,Eubacterium, and Ruminococcus. In another aspect, a therapeuticcomposition comprises two or more genera selected from the groupconsisting of Coprococcus, Dorea, Eubacterium, and Ruminococcus. In afurther aspect, a therapeutic composition comprises one or more, two ormore, three or more, four or more, or five or more species selected fromthe group consisting of Coprococcus catus. Coprococcus comes, Dorealongicatena, Eubacterium eligens, Eubacterium hadrum, Eubacteriumhallii, Eubacterium rectale, and Ruminococcus torques.

In one aspect, a therapeutic composition comprises at least about 10⁵,10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³ cfu or total cell count.In another aspect, a therapeutic composition comprises at most about10⁵, 10⁶, 10⁷, 10 ⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², 10¹³ or 10¹⁴ cfu or totalcell count.

In another aspect, a therapeutic composition comprises at least about10⁵, 10⁶, 10⁷, 10⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², or 10¹³ cells or total cellcount. In another aspect, a therapeutic composition comprises at mostabout 10⁵, 10⁶, 10⁷, 10 ⁸, 10⁹, 10¹⁰, 10¹¹, 10¹², 10¹³ or 10¹⁴ cells ortotal cell count.

In one aspect, a therapeutic composition is formulated as an oralcapsule, microcapsule, tablet, or pill. In another aspect, a capsule,microcapsule, tablet, or pill is adapted for enteric delivery. In afurther aspect, a capsule, microcapsule, tablet, or pill is an entericcapsule, microcapsule, tablet, or pill. In another aspect, a capsule,microcapsule, tablet, or pill comprises an enteric coating, is acidresistant, or both.

In one aspect, this application provides for the following embodiments:

Embodiment 1. A method for treating recurrent diverticulitis in asubject in need thereof, said method comprising administering to saidsubject a pharmaceutically active dose of a therapeutic compositioncomprising live non-pathogenic fecal bacteria or a non-cellular fecalfiltrate.

Embodiment 2. The method of claim 1, wherein said recurrentdiverticulitis is at a clinical stage selected from the group consistingof Stages I to IV.

Embodiment 3. The method of claim 1, wherein said composition comprisesan isolated or purified population of said live non-pathogenic fecalbacteria.

Embodiment 4. The method of claim 1, wherein said composition comprisesa non-selected fecal microbiota.

Embodiment 5. The method of claim 1, wherein said administration is on adaily basis.

Embodiment 6. The method of claim 1, wherein said administration lastsat least 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 weeks.

Embodiment 7. The method of claim 1, wherein said dose is administeredat least once daily or at least once weekly for at least 2, 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days or weeks.

Embodiment 8. The method of claim 1, wherein said dose is administeredat least once daily or at least once weekly for at least 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 consecutive weeks.

Embodiment 9. The method of claim 1, wherein said dose is administeredat least once daily or at least once weekly for at most 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days orweeks.

Embodiment 10. The method of claim 1, wherein said dose is administeredat least once daily or at least once weekly for at most 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 consecutive weeks.

Embodiment 11. The method of claim 1, wherein said dose is administeredat least twice daily or at least twice weekly for at least twoconsecutive days or weeks.

Embodiment 12. The method of claim 11, wherein said dose is administeredat least twice daily or at least twice weekly for at least 3, 4, 5, 6,7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days or weeks.

Embodiment 13. The method of claim 11, wherein said dose is administeredat least twice daily or at least twice weekly for at least 1, 2, 3, 4,5, 6, 7, 8, 9, 10, 11, or 12 consecutive weeks.

Embodiment 14. The method of claim 11, wherein said dose is administeredat least twice daily or at least twice weekly for at most 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20 consecutive days orweeks.

Embodiment 15. The method of claim 11, wherein said dose is administeredat least twice daily or at least twice weekly for at most 1, 2, 3, 4, 5,6, 7, 8, 9, 10, 11, or 12 consecutive weeks.

Embodiment 16. The method of claim 1, wherein said dose is administeredat least three times daily or at least three times weekly for at leastone day or week.

Embodiment 17. The method of claim 16, wherein said dose is administeredat least three times daily or at least three times weekly for at least2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days orweeks.

Embodiment 18. The method of claim 16, wherein said dose is administeredat least three times daily or at least three times weekly for at most 2,3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 consecutive days orweeks.

Embodiment 19. The method of claim 1, wherein therapeutic compositioncomprising both live non-pathogenic fecal bacteria and a non-cellularfecal filtrate.

Embodiment 20. The method of claim 1, wherein therapeutic compositioncomprising live non-pathogenic fecal bacteria supplemented with anon-cellular fecal filtrate.

Embodiment 21. The method of claim 1, 19, or 20, wherein saidnon-cellular fecal filtrate comprises biologically active proteins orpeptides, micronutrients, fats, sugars, small carbohydrates, traceelements, mineral salts, ash, mucous, amino acids, nutrients, vitamins,minerals, or any combination thereof.

Embodiment 22. The method of claim 1, 19, or 20, wherein saidnon-cellular fecal filtrate comprises one or more biologically activemolecules selected from the group consisting of bacteriocin, lanbiotic,and lacticin.e

Embodiment 23. The method of claim 1, 19, or 20, wherein saidnon-cellular fecal filtrate comprises one or more bacteriocins selectedfrom the group consisting of colicin, troudulixine, putaindicine,microcin, and subtilosin A.

Embodiment 24. The method of claim 1, 19, or 20, wherein saidnon-cellular fecal filtrate comprises one or more lanbiotics selectedfrom the group consisting of thuricin, nisin, subtilin, epidermin,mutacin, mersacidin, actagardine, and cinnamycin.

Embodiment 25. The method of claim 1, 19, or 20, wherein saidnon-cellular fecal filtrate comprises an anti-spore compound, anantimicrobial compound, an anti-inflammatory compound, or anycombination thereof.

Embodiment 26. The method of claim 1, 19, or 20, wherein saidnon-cellular fecal filtrate comprises an interleukin, a cytokine, aleukotriene, an eicosanoid, or any combination thereof.

Embodiment 27. The method of any one of preceding claims, wherein saidmethod comprises a first dosing schedule followed by a second dosingschedule.

Embodiment 28. The method of claim 27, wherein said second dosingschedule comprises a maintenance dose lower or equal to the dose of saidfirst dosing schedule.

Embodiment 29. The method of claim 28, wherein said second dosingschedule lasts for at least about 2, 4, 6, 8, 10, 12, 18, 24, 36, 48,72, or 96 months.

Embodiment 30. The method of claim 28, wherein said second dosingschedule lasts permanently.

Embodiment 31. The method of claim 27, wherein the interval between saidfirst and second dosing schedules is at least about 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, or 12 weeks.

Embodiment 32. The method of claim 27, wherein said second dosingschedule is an continuous dosing schedule.

Embodiment 33. The method of claim 27, wherein said second dosingschedule is an intermittent dosing schedule.

Embodiment 34. The method of claim 33, wherein said intermittent dosingschedule comprises a treatment period of at least 1, 2, 3, 4, 5, 6, 7,8, 9, 10, 11, 12, 13, or 14 days followed by a resting period of atleast 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, or 14 days.

Embodiment 35. The method of any one of preceding claims, wherein saidcomposition is formulated as a delayed or gradual enteric release form.

Embodiment 36. The method of any one of preceding claims, wherein saidadministering comprises administering orally, by enema, or via rectalsuppository.

Embodiment 37. The method of any one of preceding claims, wherein saidcomposition is formulated as an enteric coated capsule, anacid-resistant, enteric-coated capsule, an enteric coated microcapsule,or formulated as part of a food, a food additive, a dairy-based product,a soy-based product or a derivative thereof, a jelly, or a yogurt.

Embodiment 38. The method of any one of preceding claims, wherein saidmethod eliminates or reduces gastrointestinal dysbiosis.

Embodiment 39. The method of any one of preceding claims, wherein saidmethod increase bacterial diversity in said subject's gastrointestinaltract.

Embodiment 40. The method of any one of preceding claims, wherein saidpharmaceutically active dose comprises at least about 105, 106, 107,108, 109, 1010, 1011, 1012, or 1013 cfu or total number of cells.

Embodiment 41. The method of claim 1, wherein said pharmaceuticallyactive dose comprises at most about 105, 106, 107, 108, 109, 1010, 1011,1012, or 1013 cfu or total number of cells.

Embodiment 42. The method of claim 1, wherein said pharmaceuticallyactive dose is selected from the group consisting of from 105 to 1014,from 106 to 1014, from 107 to 1014, from 108 to 1014, from 109 to 1013,from 1010 to 1012, from 109 to 1014, from 109 to 1012, from 109 to 1011,from 109 to 1010, from 1010 to 1014, from 1010 to 1013, from 1011 to1014, from 1011 to 1013, from 1012 to 1014, and from 1013 to 1014 cfu ortotal number of cells.

Embodiment 43. The method of claim 1, wherein said composition comprisesa fecal microbiota further supplemented with a fecal microorganism.

Embodiment 44. The method of claim 43, wherein said fecal microorganismis selected from the group consisting of a Bacteroides fragilis ssp.vulgatus, Collinsella aerofaciens, Bacteroides fragilis ssp.thetaiotaomicron, Peptostreptococcus productus II, Parabacteroidesdistasonis, Fusobacterium prausnitzii, Coprococcus eutactus, Collinsellaaerofaciens III, Peptostreptococcus productus I, Ruminococcus bromii,Bifidobacterium adolescentis, Gemmiger formicilis, Bifidobacteriumlongum, Eubacterium siraeum, Ruminococcus torques, Eubacterium rectale,Eubacterium eligens, Bacteroides eggerthii, Clostridium leptum,Bacteroides fragilis ssp. A, Eubacterium biforme, Bifidobacteriuminfantis, Eubacterium rectale Coprococcus comes, Pseudoflavonifractorcapillosus, Ruminococcus albus, Dorea formicigenerans, Eubacteriumhallii, Eubacterium ventriosum I, Fusobacterium russi, Ruminococcusobeum, Eubacterium rectale, Clostridium ramosum, Lactobacillusleichmannii, Ruminococcus callidus, Butyrivibrio crossotus,Acidaminococcus fermentans, Eubacterium ventriosum, Bacteroides fragilisssp. fragilis, Bacteroides AR, Coprococcus catus, Aerostipes hadrus,Eubacterium cylindroides, Eubacterium ruminantium, Eubacterium CH-1,Staphylococcus epidermidis, Peptostreptococcus BL, Eubacterium limosum,Tissirella praeacuta, Bacteroides L, Fusobacterium mortiferum I,Fusobacterium naviforme, Clostridium innocuum, Clostridium ramosum,Propionibacterium acnes, Ruminococcus flavefaciens, Ruminococcus AT,Peptococcus AU-1, Bacteroides fragilis ssp. ovatus, -ssp. d, -ssp. f;Bacteroides L-1, L-5; Fusobacterium nucleatum, Fusobacterium mortiferum,Escherichia coli, Gemella morbillorum, Finegoldia magnus, Peptococcus G,-AU-2; Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus COGemmiger X, Coprococcus BH, —CC; Eubacterium tenue, Eubacterium ramulus,Bacteroides clostridiiformis ssp. clostridliformis, Bacteroidescoagulans, Prevotella oralis, Prevotella ruminicola, Odoribactersplanchnicus, Desuifomonas pigra, Lactobacillus G, Succinivibrio A, anda combination thereof.

Embodiment 45. The method of claim 4, wherein said fecal microbiota isfurther supplemented with bacterial spores.

Embodiment 46. The method of claim 45, wherein said bacterial spores areClostridium spores or Bacillus spores.

Embodiment 47. The method of claim 4, wherein the preparation of saidfecal microbiota involves a treatment selected from the group consistingof ethanol treatment, detergent treatment, heat treatment, irradiation,and sonication.

Embodiment 48. The method of claim 4, wherein the preparation of saidfecal microbiota involves no treatment selected from the groupconsisting of ethanol treatment, detergent treatment, heat treatment,irradiation, and sonication.

Embodiment 49. The method of claim 4, wherein the preparation of saidfecal microbiota involves a separation step selected from the groupconsisting of density gradients, filtration, and chromatography.

Embodiment 50. The method of claim 4, wherein the preparation of saidfecal microbiota involves no separation step selected from the groupconsisting of density gradients, filtration, and chromatography.

Embodiment 51. The method of claim 4, wherein said fecal microbiotacomprises a donor's entire fecal microbiota.

Embodiment 52. The method of claim 4, wherein said composition issubstantially free of eukaryotic cells from said fecal microbiota'sdonor.

Embodiment 53. The method of claim 4, wherein said fecal microbiota isfrom reconstituted fecal material.

Embodiment 54. The method of claim 4, wherein said fecal microbiota isfrom synthetic fecal material.

Embodiment 55. The method of claim 4, wherein said fecal microbiotacomprises no antibiotic resistant population.

Embodiment 56. The method of claim 4, wherein said fecal microbiotacomprises a preparation of viable flora in proportional content thatresembles a normal healthy human fecal flora.

Embodiment 57. The method of claim 4, wherein said fecal microbiotacomprises bacteria from at least seven different families.

Embodiment 58. The method of claim 4, wherein said fecal microbiota hasa Shannon Diversity Index of 0.4-5.0.

Embodiment 59. The method of claim 4, wherein said fecal microbiotacomprises one or more microorganisms selected from the group consistingof Clostridium, Bacillus, Collinsella, Bacteroides, Eubacterium,Fusobacterium, Propionibacterium, Lactobacillus, Ruminococcus,Escherichia coli, Gemmiger, Desulfomonas, Peptostreptococcus,Bifidobacterium, and Monilia.

Embodiment 60. The method of claim 4, wherein said fecal microbiotacomprises no viable Bacteroides, Fusobacterium, Propionibacterium,Lactobacillus, Ruminococcus, Escherichia coli, Gemmiger, Desulfomonas,Peptostreptococcus, Bifidobacterium, Monilia, or any combinationthereof.

Embodiment 61. The method of claim 4, wherein said fecal microbiotacomprises one or more microorganisms selected from the group consistingof a Bacteroides fragilis ssp. vulgatus, Collinsella aerofaciens,Bacteroides fragilis ssp. thetaiotaomicron, Peptostreptococcus productusII, Parabacteroides distasonis, Fusobacterium prausnitzii, Coprococcuseutactus, Collinsella aerofaciens III, Peptostreptococcus productus I,Ruminococcus bromii, Bifidobacterium adolescentis, Gemmiger formicilis,Bifidobacterium longum, Eubacterium siraeum, Ruminococcus torques,Eubacterium rectale, Eubacterium eligens, Bacteroides eggerthii,Clostridium leptum, Bacteroides fragilis ssp. A, Eubacterium biforme,Bifidobacterium infantis, Eubacterium rectale III-F, Coprococcus comes,Pseudoflavonifractor capillosus, Ruminococcus albus, Doreaformicigenerans, Eubacterium hallii, Eubacterium ventriosum I,Fusobacterium russi, Ruminococcus obeum, Eubacterium rectale,Clostridium ramosum, Lactobacillus leichmannii, Ruminococcus callidus,Butyrivibrio crossotus, Acidaminococcus fermentans, Eubacteriumventriosum, Bacteroides fragilis ssp. fragilis, Bacteroides AR,Coprococcus catus, Aerostipes hadrus, Eubacterium cylindroides,Eubacterium ruminantium, Eubacterium CH-1, Staphylococcus epidermidis,Peptostreptococcus BL, Eubacterium limosum, Tissirella praeacuta,Bacteroides L, Fusobacterium mortiferum I, Fusobacterium naviforme,Clostridium innocuum, Clostridium ramosum, Propionibacterium acnes,Ruminococcus flavefaciens, Ruminococcus AT, Peptococcus AU-1,Bacteroides fragilis ssp. ovatus, -ssp. d, -ssp. f; Bacteroides L-1,L-5; Fusobacterium nucleatum, Fusobacterium mortiferum, Escherichiacoli, Gemella morbillorum, Finegoldia magnus, Peptococcus G, -AU-2;Streptococcus intermedius, Ruminococcus lactaris, Ruminococcus COGemmiger X, Coprococcus BH, —CC; Eubacterium tenue, Eubacterium ramulus,Bacteroides clostridiiformis ssp. clostridliformis, Bacteroidescoagulans, Prevotella oralis, Prevotella ruminicola, Odoribactersplanchnicus, Desuifomonas pigra, Lactobacillus G, Succinivibrio A, anda combination thereof.

Embodiment 62. The method of claim 1, wherein said composition comprisesat least about 20%, 30%, 40%, 50%, 60%, 70%, 80%, 85%, 90%, 95%, 99%, or99.5% bacterial spores.

Embodiment 63. The method of claim 1, wherein said composition is in aliquid, frozen, freeze-dried, spray-dried, lyophilized, or powder form.

Embodiment 64. The method of claim 1, wherein said composition comprisesan excipient, a saline, a buffer, a buffering agent, or afluid-glucose-cellobiose agar (RGCA) media.

Embodiment 65. The method of claim 1, wherein said composition comprisesa cryoprotectant.

Embodiment 66. The method of claim 65, wherein said cryoprotectantcomprises polyethylene glycol, skim milk, erythritol, arabitol,sorbitol, glucose, fructose, alanine, glycine, proline, sucrose,lactose, ribose, trehalose, dimethyl sulfoxide (DMSO), glycerol, or acombination thereof.

Embodiment 67. The method of claim 1, wherein said composition furthercomprises an acid suppressant, an antacid, an H2 antagonist, a protonpump inhibitor or a combination thereof.

Embodiment 68. The method of claim 1, wherein said composition issubstantially free of non-living matter.

Embodiment 69. The method of claim 1, wherein said composition issubstantially free of acellular material selected from the groupconsisting of residual fiber, DNA, viral coat material, and non-viablematerial.

Embodiment 70. The method of claim 1, wherein said composition isformulated as an enteric coated capsule or microcapsule, anacid-resistant capsule or microcapsule, a powder suitable forreconstitution, a naso-duodenal infusion, or for delivery in the form ofan enema or a colonoscopic infusion.

Embodiment 71. The method of claim 1, wherein said composition isadministered together with a food, a liquid beverage, a food additive, adairy-based product, a soy-based product or a derivative thereof, ajelly, or a yogurt.

Embodiment 72. The method of claim 1, wherein said subject is pretreatedwith an antibiotic prior to administration of said composition.

Embodiment 73. The method of claim 72, wherein said antibiotic isselected from the group consisting of rifabutin, clarithromycin,clofazimine, vancomycin, rifampicin, nitroimidazole, chloramphenicol,and a combination thereof.

Embodiment 74. The method of claim 72, wherein said antibiotic isselected from the group consisting of rifaximin, rifamycin derivative,rifampicin, rifabutin, rifapentine, rifalazil bicozamycin,aminoglycoside, gentamycin, neomycin, streptomycin, paromomycin,verdamicin, mutamicin, sisomicin, netilmicin, retymicin, kanamycin,aztreonam, aztreonam macrolide, clarithromycin, dirithromycin,roxithromycin, telithromycin, azithromycin, bismuth subsalicylate,vancomycin, streptomycin, fidaxomicin, amikacin, arbekacin, neomycin,netilmicin, paromomycin, rhodostreptomycin, tobramycin, apramycin, and acombination thereof.

Embodiment 75. The method of any one of preceding claims, wherein saidsubject is pretreated with an anti-inflammatory drug prior toadministration of said composition.

Embodiment 76. The method of any one of preceding claims, wherein saidcomposition comprises non-pathogenic spores of one or more, two or more,three or more, or four or more Clostridium species selected from thegroup consisting of Clostridium absonum, Clostridium argentinense,Clostridium baratii, Clostridium botulinum. Clostridium cadaveris,Clostridium carnis, Clostridium celatum, Clostridium chauvoei,Clostridium clostridioforme, Clostridium cochlearium, Clostridiumfallax, Clostridium felsineum, Clostridium ghonii, Clostridiumglycolicum, Clostridium haemolyticum, Clostridium hastiforme,Clostridium histolyticum, Clostridium indolis, Clostridium irregulare,Clostridium limosum, Clostridium malenominatum, Clostridium novyi,Clostridium oroticum, Clostridium paraputrificum, Clostridiumperfringens, Clostridium piliforme, Clostridium putrefaciens,Clostridium putrificum, Clostridium sardiniense, Clostridiumsartagoforme, Clostridium scindens, Clostridium septicum, Clostridiumsordellii, Clostridium sphenoides, Clostridium spiroforme, Clostridiumsporogenes, Clostridium subterminale, Clostridium symbiosum, Clostridiumtertium, Clostridium tetani, Clostridium welchii, and Clostridiumvillosum.

Embodiment 77. The method of claim 1, wherein said composition comprisespurified, isolated, or cultured viable non-pathogenic Clostridium and aplurality of purified, isolated, or cultured viable non-pathogenicmicroorganisms from one or more genera selected from the groupconsisting of Collinsella, Coprococcus, Dorea, Eubacterium, andRuminococcus.

Embodiment 78. The method of claim 1, wherein said composition comprisesa plurality of purified, isolated, or cultured viable non-pathogenicmicroorganisms from one or more genera selected from the groupconsisting of Clostridium, Collinsella, Coprococcus, Dorea, Eubacterium,and Ruminococcus.

Embodiment 79. The method of claim 77, wherein said compositioncomprises two or more genera selected from the group consisting ofCollinsella, Coprococcus, Dorea, Eubacterium, and Ruminococcus.

Embodiment 80. The method of claim 77, wherein said compositioncomprises two or more genera selected from the group consisting ofCoprococcus, Dorea, Eubacterium, and Ruminococcus.

Embodiment 81. The method of claim 77 or 78, wherein said plurality ofviable non-pathogenic microorganisms comprise one or more, two or more,three or more, four or more, or five or more species selected from thegroup consisting of Coprococcus catus, Coprococcus comes, Dorealongicatena, Eubacterium eligens, Eubacterium hadrum, Eubacteriumhallii, Eubacterium rectale, and Ruminococcus torques.

Embodiment 82. The method of any one of preceding claims, wherein saidmethod eliminates or reduces one or more recurrent diverticulitissymptoms selected from the group consisting of left lower quadrant pain,shifting bowel habits, nausea, vomiting, constipation, diarrhea,flatulence, and bloating, abscess, phlegmon, fistula, stricture,stenosis, obstruction, bleeding, and perforation.

Embodiment 83. The method of any one of preceding claims, wherein saidmethod further comprises administering a 5-aminosalicylic acid agent, acorticosteroid, an immunosuppressant, or a combination thereof.

Embodiment 84. The method of any one of preceding claims, wherein saidmethod further comprises administering 5-aminosalicylic acid or aderivative thereof, Sulfasalazine or a derivative thereof, or acombination thereof.

EXAMPLES Example 1 Preparation of Fecal Microbiota

Fecal microbiota is prepared essentially according to protocolspublished in US2014/0147417 or WO2014/152484. Summarized below is anexemplary protocol.

Potential fecal microbiota donors are screened according to a list ofcriteria used to exclude unsuitable donors. Potential fecal microbiotadonors are excluded if they have received antibiotics, laxatives, dietpills, immunomodulators or chemotherapy in the preceding three months.Potential fecal microbiota donors are excluded if they have a history ofall known infectious diseases, morbid obesity, diabetes, irritable bowelsyndrome, inflammatory bowel disease, chronic diarrhea, constipation,colorectal polyps or cancer, a compromised immune system, metabolicsyndromes, chronic fatigue syndrome, major GI surgery, or other diseasesor conditions potentially associated with specific changes in fecalmicrobiota. Potential fecal microbiota donors are excluded if theyexhibit positive laboratory tests for C-reactive protein, erythrocytesedimentation rate, hepatitis A, hepatitis B, hepatitis C, humanimmunodeficiency virus, or syphilis. Potential fecal microbiota donorsare excluded if they exhibit a positive test for stool ova or parasites.Potential fecal microbiota donors are excluded if they engage inhigh-risk sexual behaviors, have been incarcerated, or received anytattoos or body piercings in areas that have had disease epidemicswithin the past three months.

Donor fecal material (fresh feces) is collected in a sterilizedcontainer, then it is transferred to a blender. Approximately 500-1000mL 0.9% saline solution is added to the blender and thoroughly mixedwith the fecal sample. The resulting suspension is filtered at least 4times through strainers prior to collecting a final suspension. Thefinal suspension is centrifuged in 50 mL tubes at 1200×g for 3 minutes.The supernatant is discarded and the pellet is gently resuspended inapproximately 50 mL of sterile 0.9% saline solution. The centrifugationand resuspension steps are repeated 2 to 4 additional times. Upon thefinal centrifugation, the supernatant is discarded. If the fecalmicrobiota is to be used immediately, the resultant pellet isresuspended in 1.5-volumes of 0.9% saline solution by gently mixing. Ifthe fecal microbiota is to be stored, the resultant pellet isresuspended in 10% sterile glycerol and stored at −80 degreesCentigrade. If fecal microbiota are frozen, they are warmed to roomtemperature prior to administration to a patient. If fecal microbiota islyophilized, the lyoprotectant formulation and lyophilization procedurefollow essentially those described in US 2016/0331791, published Nov.17, 2016.

Example 2 Treatment of Recurrent Diverticulitis with FMT

A first, 67 year old patient experienced high-frequency recurrentattacks of diverticulitis. At times, his recurrent attacks occurred onalmost a monthly basis which resulted in frequent emergency room visitsand intravenous administration of antibiotics. The attacks recurreddespite him being on antibiotic prophylaxis, mesalamine therapy, orsalazopyrin treatment. The patient eventually resorted to FecalMicrobiota Transplantation (FMT). He was given a five day infusion ofliquid, homogenized fresh donor stool which was initially infusedthrough a colonoscope and later via four enema infusions. At the 3-monthcheck-up following the infusions, the patient reported no furtherattacks and at the twelve-month check-up, there was no recurrent attackof diverticulitis. At the last review five years after the FMT, he wasfree of any recurrent diverticulitis in spite of the fact that hecontinued to have what appeared to be quite extensive diverticulardisease previously documented by colonoscopy and CT scan.

A second, 59-year-old female patient suffered from recurrentdiverticulitis. On one occasion, she had developed a peri-diverticularabscess and had a prolonged stay in hospital. She was advised to have acolectomy of the area where the diverticulitis was present. The patientrefused to undergo resection of sigmoid colon with diverticulae. Sheslowly recovered, became virtually asymptomatic, and left the hospital.However, in a short while, she continued to have relapsing attacks ofdiverticulitis taking her to hospital every few months. She wasultimately referred for assessment for prophylactic treatment. Varioustreatments were attempted with little success, including treatment forconstipation using oral vancomycin, rifaximin to suppress bloating,laxatives, and olsalazine—all of which had previously been asserted tomarginally reduce recurrent diverticulitis. Finally, the patientreceived Fecal Microbiota Transplantation and she underwent fiveinfusions. The first infusion was done by colonosocpe and then by rectalinfusion. She experienced no further attacks for three years. Afterthree years, however, she suffered another attack of diverticulitis.

A third, 71-year-old female patient was referred by a surgeon for FMTbecause of recurrent diverticulitis. This patient was not well enough toundergo resection of her left colon due to other co-morbidities. Thepatient underwent a five day FMT infusion treatment with the initialinfusion via a colonoscope and then with enemas of fresh donor stoolhomogenized to a liquid format. She then underwent ‘top up’ infusionsevery week for 4 weeks. Her recurrent diverticular disease resolved forthree years at the time of follow up.

Example 3 Oral Capsule Treatment Protocol (Short Regimen) for RecurrentDiverticulitis

Patients are divided into four groups (Groups 1 to 4). Group 1 patientsare administered a pre-treatment of antibiotics (e.g., Vancomycin,Metronidazole, and Colchicine) until the patient shows signs of improvedbowel movements. Group 2 receives no antibiotics. Both Groups 1 and 2receive a pre-colonoscopy bowel prep followed by capsule FMT. Groups 3and 4 receive no bowel prep while Group 3, not group 4, also receive anantibiotic pretreatment. Capsules are administered for 2 weeks asfollows: two capsules (each containing 10⁹ to 10¹¹ bacterial organisms),given twice-a-day for 4 days, two capsules twice-a-day every other dayfor 10 days. High dose capsules (total cell count of about 10¹²) areused in loading doses (also called treatment doses) for the initial 4days. Lower dose capsules (total cell count of about 10⁹) are used inmaintenance doses for the subsequent 10 days. In patients receivingantibiotic pretreatment, capsules are administered one day after ceasingantibiotics. Patient symptoms are observed and clinical examination isperformed before, during and post oral capsule treatment. Pre, duringand post-treatment DNA metagenomics (2-4 days; 1 week; 6 weeks; 12weeks) are also carried out.

Example 4 Oral Capsule Treatment Protocol (Long Regimen) for RecurrentDiverticulitis

Patients are divided into four groups (Groups 1 to 4). Group 1 patientsare administered a pre-treatment of antibiotics (e.g., Vancomycin,Metronidazole, and Colchicine if constipation is an issue) until thepatient shows signs of improved bowel movements. Group 2 receives noantibiotics. Both Groups 1 and 2 receive a pre-colonoscopy bowel prepfollowed by capsule FMT. Groups 3 and 4 receive no bowel prep whileGroup 3, not group 4, also receive an antibiotic pretreatment. Capsulesare administered for 18 weeks or more, as follows: two capsulestwice-a-day for 14 days, two capsules twice-a-day every other day for 14days, 4 capsules twice-a-week for 14 days, and 4 capsules once-a-week(e.g., each Monday) for 12 weeks. High dose capsules (total cell countof about 10¹²) are used in loading doses (also called treatment doses)for the initial 4 weeks. Lower dose capsules (total cell count of about10⁹) are used in maintenance doses for the subsequent 14 weeks. Inpatients receiving antibiotic pretreatment, capsules are administeredone day after ceasing antibiotics. Patient symptoms are observed andclinical examination is performed before, during and post oral capsuletreatment. Pre, during and post-treatment DNA metagenomics (2-4 days; 1week; 6 weeks; 12 weeks) are also carried out.

As various modifications could be made in the constructions and methodsherein described and illustrated without departing from the scope of thedisclosure, it is intended that all matter contained in the foregoingdescription shall be interpreted as illustrative rather than limiting.The breadth and scope of the present disclosure should not be limited byany of the above-described exemplary embodiments, but should be definedonly in accordance with the following claims appended hereto and theirequivalents. All patent and non-patent documents cited in thisspecification are incorporated herein by reference in their entirety.

The invention claimed is:
 1. A method for treating recurrentdiverticulitis in a subject in need thereof, said method comprisingadministering to said subject a pharmaceutically active dose of atherapeutic composition comprising a community of fecal bacteria derivedfrom a stool of a healthy human donor, wherein the therapeuticcomposition further comprises a cultured bacterial isolate.
 2. Themethod of claim 1, wherein said recurrent diverticulitis is at aclinical stage selected from the group consisting of Stages I to IV. 3.The method of claim 1, wherein said community of fecal bacteriacomprises a non-selected fecal microbiota.
 4. The method of claim 1,wherein said dose is administered at least once daily for at least 2weeks.
 5. The method of claim 1, wherein said dose is administered atleast twice weekly for at least 2 weeks.
 6. The method of claim 1,wherein said dose is administered at least twice weekly for at least 4weeks.
 7. The method of claim 1, wherein said dose is administered atleast twice weekly for at least 8 weeks.
 8. The method of claim 1,wherein said dose is administered at least three times weekly for atleast 4 weeks.
 9. The method of claim 1, wherein said method comprises afirst dosing schedule followed by a second dosing schedule, wherein saidsecond dosing schedule comprises a maintenance dose lower than the doseof said first dosing schedule.
 10. The method of claim 1, wherein saidcomposition is formulated as a delayed or gradual enteric release form.11. The method of claim 1, wherein said composition is formulated as anenteric coated capsule or an acid-resistant capsule.
 12. The method ofclaim 1, wherein said pharmaceutically active dose is from 10⁸ to 10¹⁴cfu or total number of cells.
 13. The method of claim 3, wherein saidfecal microbiota comprises an entire fecal microbiota of said stool orportion thereof.
 14. The method of claim 1, wherein said composition isin a liquid, frozen, freeze-dried, spray-dried, lyophilized, or powderform.
 15. The method of claim 1, wherein said composition comprises acryoprotectant selected from the group consisting of polyethyleneglycol, skim milk, erythritol, arabitol, sorbitol, glucose, fructose,alanine, glycine, proline, sucrose, lactose, ribose, trehalose, dimethylsulfoxide (DMSO), glycerol, and a combination thereof.
 16. The method ofclaim 15, wherein said cryoprotectant comprises trehalose.
 17. Themethod of claim 1, wherein said subject is pretreated with an antibioticprior to administration of said composition.
 18. The method of claim 1,wherein said method eliminates or reduces one or more recurrentdiverticulitis symptoms selected from the group consisting of left lowerquadrant pain, shifting bowel habits, nausea, vomiting, constipation,diarrhea, flatulence, bloating, abscess, phlegmon, fistula, stricture,stenosis, obstruction, bleeding, and perforation.
 19. The method ofclaim 1, wherein said method further comprises administering a5-aminosalicylic acid agent, a corticosteroid, an immunosuppressant, ora combination thereof.